The vitamin D3 endocrine system, besides playing pivotal roles in calcium homeostasis and bone mineral metabolism, is recognized to play a pivotal role in a wide range of fundamental biological functions, and especially in cell differentiation, inhibition of cell growth, and immune function. Vitamin D3 (cholecalciferol) is considered a prohormone, which is converted into the more active form 25-hydroxyvitamin D3 (calcidiol), which in turn is converted into the hormonal form 1,25-hydroxyvitamin D3 (calcitriol) in selected tissues. Calcitriol then binds and activates the cellular Vitamin D3 receptor (VDR) to modulate gene transcription and regulate mineral ion homeostasis. Abrogation of gene activation by VDR action is thought to be under the control of the calcitriol metabolizing enzyme 24-hydroxylase that inactivates calcitriol.
As the VDR receptor (and various isoforms) and the corresponding metabolic enzymes are expressed in many tissues, it is assumed that calcitriol can act in an autocrine, paracrine, or intracrine fashion to affect the biology of non-classical target tissues. For example, production of both the activating and the metabolizing enzymes by cells of the immune system suggests that calcitriol can be locally produced in immune reaction sites. Indeed, recent studies have shown moderate immunosuppressive effect of calcitriol. Other studies have shown that calcitriol may act as a potent antiproliferative agent. For example, Vitamin D deficiency is suspected to raise the risk of prostate cancer, most likely via the VDR but possibly also through its 1-alpha-hydroxylation in the prostate. Similarly, calcitriol is a coordinate regulator of proliferation, differentiation, and survival of breast cancer cells. In addition, epidemiologic, clinical, and animal studies suggested that vitamin D status is important for protection against the development of breast cancer. Therefore, vitamin D compounds that bind and activate VDRs offer promise as therapeutic agents for the treatment of established breast cancer.
To increase levels of calcitriol, various attempts have been undertaken. Most commonly, dietary supplementation using Vitamin D3 (cholecalciferol) is considered a viable option to raise cholecalciferol levels with the expectation that an upstream surplus of substrate will ultimately lead to the production of the calcitriol form. Unfortunately, calcitriol synthesis and degradation are tightly regulated processes, and no significant increase in calcitriol can be achieved using administration of cholecalciferol. Similarly, U.S. Pat. App. No. 2005/0032743 teaches use of low-dose administration of selected boron-containing compounds together with cholecalciferol to raise levels of calcidiol (25-hydroxyvitamin D3) in human, presumably via inhibition of the conversion of the calcidiol to calcitriol. It should be noted that in this publication, calcidiol (but not calcitriol) was described as the ‘active form’ of vitamin D3. In still other attempts, calcitriol is directly administered (ROCALTROL™; 1,25-dihydroxycholecalciferol, commercially available by Roche) to increase calcitriol serum concentration. However, oral administration of calcitriol is associated with a plethora of undesirable side effects, including hypercalcemia, excessive thirst and sweating, nausea, and constipation.
Thus, while numerous compositions and methods of modulating calcitriol concentrations in serum are known in the art, all of almost all of them suffer from one or more disadvantages. Consequently, there is still a need to provide improved compositions and methods to modulate the concentration of calcitriol in a mammal, and especially in a human.